Utilization of [2 + 1] cycloaddition reactions of 1-seleno-2- silylethenes: A novel synthesis of 2-substituted 1-aminocyclopropane-1- carboxylic acids

Full text of DOI:10.1021/jo9810821

282
J . Org. Chem. 1999, 64, 282-286
utilizing the functionality masked in its structure. Com-
Utiliza tion of [2 + 1] Cycloa d d ition
pound 3 is shown to be a general synthetic intermediate
for (E)-2-substituted ACC derivatives such as (()-coro-
namic acid and its alkyl derivative and a 2,3-methano-
aspartic acid derivative.
Rea ction s of 1-Selen o-2-silyleth en es: A
Novel Syn th esis of 2-Su bstitu ted
1-Am in ocyclop r op a n e-1-ca r boxylic Acid s
Shoko Yamazaki,* Takashi Inoue, Taro Hamada, and
Takashi Takada
Resu lts a n d Discu ssion
The selenium- and silicon-containing cyclopropane 3
was prepared along with the cyclobutane byproduct 4 (3:4
) ca. 7:3) by the reaction of 1-(phenylseleno)-2-(trieth-
ylsilyl)ethene (1) and di-tert-butyl methylenemalonate (2)
in the presence of ZnBr2 in high total yield (90-98%),
according to the procedure described in our previous
paper (eq 1).4 Compounds 3 and 4 were also prepared by
the reaction of 1 and 2 in the presence of ZnI2 in 83%
total yield with a 3:4 ratio of ca. 7:3 under similar
conditions (-30 °C, 1.5 h, 0 °C, 0.5 h). The conversion of
the highly functionalized cyclopropane 3 into (()-coro-
namic acid (12) was next examined. After extensive
experimentation under various conditions, stereoselective
reduction of the less hindered ester function trans to the
(phenylseleno)(triethylsilyl)methyl group in 3 to yield
alcohol 6 was performed by a two-step procedure as
follows. Reduction of 3 with LiAlH4 at -78 °C gave a
mixture of monoaldehyde 56 and monoalcohol 6. The
Department of Chemistry, Nara University of Education,
Takabatake-cho, Nara 630-8258, J apan
Kagetoshi Yamamoto
Department of Chemistry, Graduate School of Science,
Osaka University, Toyonaka, Osaka 560-0043, J apan
Received J une 8, 1998
In tr od u ction
Functionalized cyclopropanes are useful synthetic in-
termediates for natural and unnatural biologically active
cyclopropanes, which possess a large spectrum of biologi-
cal properties.1 Among them, 1-aminocyclopropane-1-
carboxylic acids, ACCs (2,3-methanoamino acids), are
particularly biologically important compounds.2 Their
incorporation into peptides, utilizing their conformational
restriction properties is also an active research area.2a,3
Therefore, new methodologies for synthesis of function-
alized cyclopropanes and stereoselective conversion to
substituted ACCs are much attracting attention. We have
recently reported the reaction of 1-seleno-2-silylethene
1 and methylenemalonate ester 2 in the presence of
Lewis acid to provide a highly functionalized cyclopro-
pane 3 (eq 1).4 This new approach to cyclopropane
mixture of 5 and 6 without separation was treated with
NaBH4 at -30 °C to give mono alcohol 6 in 87% yield
from 3. The high stereoselection in the mono reduction
probably derives from the bulk of the (phenylseleno)-
(triethylsilyl)methyl group.
Compound 6 was protected by the tert-butyldimethyl-
silyl (TBDMS) group to give 7 in 95% yield. NOESY
spectra for 6 and protected compound 7 confirmed the
stereochemistry.7 NOEs were observed between H2a (δ
1.48-1.54) and H3a (δ 1.20), between H2a (δ 1.48-1.54)
and CH2OH (δ 3.35 and 3.60), between H3b (δ 1.33-1.39)
and H4 (δ 2.84), and between H4 (δ 2.84) and OtBu (δ
1.44) in 6. NOEs were observed between H2a (δ 1.57) and
CHHOTBDMS (δ 3.42), between H4 (δ 2.91) and OtBu (δ
1.41), and between OtBu (δ 1.41) and o-SePh (δ 7.54-
construction is based on a selenium-stabilized 1,2-silicon
migration process.5 In this paper, the cyclopropane
product 3 is transformed to various 1-aminocyclopropane-
1-carboxylic acid (ACC) derivatives stereoselectively
(5) (a) Yamazaki, S.; Tanaka, M.; Yamaguchi, A.; Yamabe, S. J . Am.
Chem. Soc. 1994, 116, 2356. (b) Yamazaki, S.; Tanaka, M.; Yamabe,
S. J . Org. Chem. 1996, 61, 4046. (c) Yamazaki, S.; Kumagai, H.;
Takada, T.; Yamabe, S.; Yamamoto, K. J . Org. Chem. 1997, 62, 2968.
(d) Yamazaki, S.; Imanishi, T.; Moriguchi, Y.; Takada, T. Tetrahedron
Lett. 1997, 38, 6397.
(1) For reviews, see: (a) Salau¨n, J .; Baird, M. S. Curr. Med. Chem.
1995, 2, 511. (b) Liu, H. W.; Walsh, C. T. Biochemistry of the
Cyclopropyl Group. In The Chemistry of the Cyclopropyl Group;
Rappoport, Z., Ed.; Wiley: New York, 1987; p 959. (c) Elliott, M.; J anes,
N. F. Chem. Soc. Rev. 1978, 7, 473.
(2) For reviews, see: (a) Stammer, C. H. Tetrahedron 1990, 46, 2231.
(b) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994, 575. (c)
Kodama, H.; Shimohigashi, Y. Yuki Gosei Kagaku Kyokaishi 1994, 52,
180; Chem. Abstr. 1994, 120, 299214r. (d) Alami, A.; Calmes, M.;
Daunis, J .; J acquier, R. Bull. Soc. Chim. Fr. 1993, 130, 5.
(3) (a) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J . Am. Chem. Soc. 1995,
117, 54. (b) Lim, D.; Burgess, K. J . Am. Chem. Soc. 1997, 119, 9632,
and references therein.
(6) Reaction of 3 with LiAlH4 at -78 °C for 1 h and separation by
column chromatography gave 5 and 6 in 40 and 33% yields, respec-
tively. For 5: Rf ) 0.5 (hexane:ether ) 4:1); pale yellow oil (including
a trace amount of unidentified impurity); 1H NMR (200 MHz, CDCl3)
δ 0.564-0.686 (m, 9H), 0.941 (t, J ) 7.8 Hz, 6H), 1.48 (s, 9H), 1.71
(dd, J ) 7.8, 2.7 Hz, 1H), 1.91-2.07 (m, 2H), 2.94 (d, J ) 11.7 Hz,
1H), 7.22-7.25 (m, 3H), 7.50-7.55 (m, 2H), 10.10 (s, 1H); 13C NMR
(50.1 MHz, CDCl3) δ 3.2, 7.6, 24.4, 28.3, 28.5, 41.2, 43.5, 82.5, 127.9,
128.9, 129.1, 135.8, 168.1, 199.0; IR (neat) 2956, 2878, 1698 cm-1
.
(7) Stereochemistry concerning the relative configuration between
C2 and C4 (see Scheme 1 for the numbering) of 6 and 7 was assumed
as (R,R) and (S,S), which retains that of 3. The assignment of the
stereochemistry of 3 was discussed in our previous paper.4
(4) Yamazaki, S.; Tanaka, M.; Inoue, T.; Morimoto, N.; Kumagai,
H.; Yamamoto, K. J . Org. Chem. 1995, 60, 6546.
10.1021/jo9810821 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Notes
J . Org. Chem., Vol. 64, No. 1, 1999 283
Sch em e 1
general solution to (E)-2-alkyl ACC derivatives. To show
the utility of 8 as a synthetic intermediate for (E)-2-alkyl
ACC derivatives, 8 was reacted with pentylenetriphen-
ylphosphorane to give 14 in 90% yield. The same se-
quence leads to (E)-1-amino-2-hexylcyclopropane-1-car-
boxylic acid 18. Thus, diverse 2-substituted cyclopropanes
corresponding to 10 (such as 15) can be prepared by two
steps including Wittig reaction from the common inter-
mediate 8. On the other hand, using Charette’s method,
to obtain analogues of 10, diverse starting alkenes which
require multistep conversion, including the carbenoid
addition, are necessary. Therefore, our method involves
a more efficient series of manipulations than that of
Charette and has advantages for preparation of diverse
2-substituted ACC derivatives, although our method only
creates racemic products at this stage.
Next, synthesis of a protected (E)-2,3-methanoaspartic
acid was demonstrated. In the literature, stereoselective
syntheses of a (Z)-2,3-methanoaspartic acid derivative
and of a mixture of (E) and (Z)-derivatives have been
reported;2a-b,11 however, no stereoselective synthesis of
a (Z)-2,3-methanoaspartic acid derivative has been de-
scribed yet. Direct oxidation of 7 to carboxylic acid was
achieved using RuCl3-NaIO4 in CCl4-CH3CN-H2O.12,13
Thus, a selenosilylmethyl group can be considered as not
only a formyl group equivalent, but also a carboxyl group
equivalent. Treatment of the carboxylic acid with diazo-
methane in ether gave methyl ester 19 in 69% yield. A
similar procedure was applied to the synthesis of amino-
and dicarboxyl-protected (E)-2,3-methanoaspartic acid
21. For the final Curtius rearrangement, the one-step
method (diphenylphosphoryl azide (DPPA), Et3N in t-
BuOH)14 from the carboxylic acid intermediate was
adopted because of difficulty in the purification of the
azide intermediate. NOESY spectra for both 19 and 21
confirmed the stereochemistry. NOEs were observed
between H2a (δ 1.99) and H3a (δ 1.24), between H2a (δ 1.99)
and CHHOTBDMS (δ 3.69), and between OtBu (δ 1.43)
and OMe (δ 3.67) in 19. NOEs were observed between
H2a (δ 2.26) and NBoc OtBu (δ 1.46) and between ester
OtBu (δ 1.43) and OMe (δ 3.70) in 21.15 Thus, a novel
stereoselective synthesis of protected (E)-2,3-methano-
aspartic acid 21 was achieved. Since spontaneous ring
opening of the free amine forms of 2,3-methanoaspartic
acid has been reported,2a-b,16 incorporation of 2,3-metha-
noaspartic acid into peptides needs some indirect
Sch em e 2
Sch em e 3
(10) (a) Ichihara, A.; Shiraishi, K.; Sakamura, S. Tetrahedron Lett.
1977, 269. (b) Baldwin, J . E.; Adlington, R. M.; Rawlings, B. Tetrahe-
dron Lett. 1985, 26, 481. (c) Williams, R. M.; Fegley, G. J . J . Am. Chem.
Soc. 1991, 113, 8796.
(11) (a) Godier-Marc, E.; Aitken, D. J .; Husson, H.-P. Tetrahedron
Lett. 1997, 38, 4065. (b) Wick, L.; Tamm, C.; Boller, T. Helv. Chim.
Acta 1995, 78, 403. (c) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M.
Tetrahedron: Asymmetry 1996, 7, 537. (d) A single stereoisomer (12%
yield) without assignment of stereochemistry. Horikawa, H.; Nishitani,
T.; Iwasaki, T.; Inoue, I. Tetrahedron Lett. 1983, 24, 2193.
(12) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(13) The reaction can be carried out using crude 7, which was
prepared from the mixture of cyclopropane 3 and cyclobutane 4 without
separation, and was purified from the small amount of impurity arising
from 4 at this stage. See also ref 8.
(14) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151.
7.56) in 7. Compound 7 was oxidized with NaIO4 in
THF-H2O solution at room temperature to give aldehyde
8 in 73% yield.8 Wittig reaction of 8 with methylene-
triphenylphosphorane in THF gave 9 in 85% yield. Next,
9 was converted by diimide reduction to give 10 in 95%
yield (Scheme 1).
The obtained 10 is the racemic analogue of a synthetic
intermediate of (-)-coronamic acid, which was reported
by Charette.9 Compound 10 was converted to protected
coronamic acid 12, following Charette’s method (Scheme
2). Compound 12 was finally deprotected to give (()-
coronamic acid (13).10 This approach promises to be a
(15) 1H NMR chemical shifts of N-Boc OtBu and ester OtBu in 21
were assigned as follows. The N-Boc OtBu appeared as a broad singlet
and has HMBC correlation with a broad peak in 13C (80.4 ppm) which
is assigned as N-Boc OC(CH3)3. The broadening may be due the
rotation barrier of the carbamate moiety. Broadening of 13C peaks of
N-Boc CdO, N-Boc OC(CH3)3, and cyclopropyl carbons were observed
for Boc-protected ACCs, 12, 17, and 21.
(8) A two-step (LiAlH4-NaBH4) reduction starting from the mixture
of cyclopropane 3 and cyclobutane 4 without separation, subsequent
protection by tert-butylchlorodimethylsilane (TBDMSCl) and oxidation
by NaIO4 gave 8 without decreasing the yield, and 8 was isolated at
this stage. Thus, the somewhat tedious MPLC separation of 3 and 4
can be avoided.
(9) Charette, A. B.; Coˆte´, B. J . Am. Chem. Soc. 1995, 117, 12721.
(16) Taylor, E. C.; Hu, B. Synth. Commun. 1996, 26, 1041.

284 J . Org. Chem., Vol. 64, No. 1, 1999
Notes
approaches.11a,17 Incorporation of 21 and related ana-
logues into peptides is under way.
(calcd for C22H36O3SeSi 456.1599). Anal. Calcd for C22H36O3-
SeSi: C, 58.00; H, 7.96. Found: C, 58.14; H, 7.99.
(()-(Z)-ter t-Bu tyl 1-((ter t-Bu tyld im eth ylsilyl)oxy)m eth -
yl-2-[(p h en ylselen o)(t r iet h ylsilyl)m et h yl]cyclop r op a n e-
1-ca r boxyla te (7). TBDMSCl (374 mg, 2.5 mmol) was added
to a solution of 6 (757 mg, 1.7 mmol) in CH2Cl2 (15 mL), followed
by imidazole (163 mg, 2.4 mmol). The mixture was stirred for
25 h. Saturated aqueous NaHCO3 was added to the mixture.
The mixture was extracted with ether, and the organic phase
was dried (MgSO4) and evaporated in vacuo. The residue was
purified by column chromatography over silica gel eluting with
hexanes:ether to give 7 (896 mg, 95%). For 7: Rf ) 0.8 (hexane:
ether ) 4:1); colorless oil; 1H NMR (600 MHz, CDCl3) δ 0.025
(s, 3H), 0.037 (s, 3H), 0.563-0.632 (m, 6H), 0.867 (s, 9H), 0.917
(t, J ) 8.0 Hz, 9H), 1.21-1.25 (m, 2H), 1.41 (s, 9H), 1.57 (ddd,
J ) 12.4, 8.9, 7.4 Hz, 1H), 2.91 (d, J ) 12.4 Hz, 1H), 3.42 (d, J
) 10.2 Hz, 1H), 3.93 (d, J ) 10.2 Hz, 1H), 7.17-7.21 (m, 3H),
7.54-7.56 (m, 2H); selected observed NOE's were between δ
1.21-1.25 and 1.57, δ 1.21-1.25 and 2.91, δ 1.41 and 2.91, δ
1.41 and 7.54-7.56, δ 1.57 and 3.42, δ 2.91 and 7.54-7.56; 13C
NMR (50.1 MHz, CDCl3) δ -5.4 (q, J ) 119 Hz), 3.3 (t, J ) 116
Hz), 7.6 (q, J ) 124 Hz), 18.1 (s), 20.6 (t, J ) 161 Hz), 25.3 (d,
J ) 133 Hz), 25.8 (q, J ) 125 Hz), 28.1 (d, J ) 153 Hz), 28.2 (q,
J ) 126 Hz), 32.3 (s), 62.7 (t, J ) 144 Hz), 80.4 (d, J ) 4.4 Hz),
127.0 (dt, J ) 161, 7.3 Hz), 128.5 (d, J ) 157 Hz), 129.8 (s),
134.9 (d), 171.1 (s); IR (neat) 2958, 2936, 2878, 1713 cm-1; MS
(EI) m/z 570; exact mass M+ 570.2473 (calcd for C28H50O3SeSi2
570.2464). Anal. Calcd for C28H50O3SeSi2: C, 59.02; H, 8.84.
Found: C, 59.24; H, 8.89.
In summary, new methodologies for stereoselective
synthesis of (E)-2-substituted ACCs have been demon-
strated. The [2 + 1] cycloadduct derived from reaction
between 1-(phenylseleno)-2-(triethylsilyl)ethene (1) and
di-tert-butyl methylenemalonate (2) in the presence of
ZnX2 (X ) Br, I) was transformed to several ACC
derivatives stereoselectively. The selenosilylmethyl group
in 3 functioned as a stereocontrolling group for mono
reduction and as a formyl or carboxyl group equivalent.
Compound 3 can also be a general synthetic intermediate
for (Z)-2-substituted ACC derivatives by alternative
transformation of the other carboxyl group to an amino
group.9 Application of this methodology to other ami-
nocylopropanecarboxylic acid derivatives, and develop-
ment of a chiral version are currently under investigation
in our laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR spec-
tra were recorded in the FT mode. 1H NMR spectra were
recorded in CDCl3 at 200, 400, or 600 MHz. 13C NMR spectra
were recorded in CDCl3 at 50.1 or 100.6 MHz. Chemical shifts
are reported in ppm relative to Me4Si or residual nondeuterated
solvent. Mass spectra were recorded at an ionizing voltage of
70 eV by EI or FAB. All reactions were carried out under a
nitrogen atmosphere. MPLC was performed with a UV detector
at 254 nm and a flow rate of 15 mL/min using a Michel-Millor
column (20φ × 30 cm).
(()-(Z)-ter t-Bu tyl 1-((ter t-Bu tyld im eth ylsilyl)oxy)m eth -
yl-2-for m ylcyclop r op a n e-1-ca r boxyla te (8). To a solution of
7 (174 mg, 0.3 mmol) in THF (8 mL) were added water (4 mL)
and NaIO4 (332 mg, 1.6 mmol). The mixture was stirred for 6 h
at room temperature. Saturated aqueous NaHCO3 solution was
added to the reaction mixture. The mixture was extracted with
ether, and the organic phase was dried (MgSO4) and evaporated
in vacuo. The residue was purified by column chromatography
over silica gel eluting with hexanes:ether to give 8 (71 mg, 73%).
For 8: Rf ) 0.3 (hexane:ether ) 4:1); colorless oil; 1H NMR (200
MHz, CDCl3) δ 0.048 (s, 6H), 0.867 (s, 9H), 1.45 (s, 9H), 1.53
(dd, J ) 8.2, 4.3 Hz, 1H), 1.93-2.11 (m, 2H), 3.75 (d, J ) 10.4
The cyclopropane 3 was prepared according to the procedure
described in our previous paper,4 as a mixture with the cyclo-
butane byproduct 4 (3:4 ) ca. 7:3) by the reaction of 1-(phen-
ylseleno)-2-(triethylsilyl)ethene (1) and di-tert-butyl methylen-
emalonate (2) in the presence of ZnBr2 or ZnI2. Compounds 3
and 4 were separated by MPLC (Wakogel LP-60, cyclohexane:
CH2Cl2 ) 9:1). Alternatively, the mixture of 3 and 4 was used
without separation.8,13
Hz, 1H), 3.96 (d, J ) 10.4 Hz, 1H), 9.30 (d, J ) 6.1 Hz, 1H); 13
C
NMR (50.1 MHz, CDCl3) δ -5.5 (q, J ) 118 Hz), 15.9 (t, J )
166 Hz), 18.2 (s), 25.8 (q, J ) 125 Hz), 28.0 (q, J ) 127 Hz), 32.9
(dd, J ) 169, 26 Hz), 35.9 (s), 61.8 (t, J ) 144 Hz), 82.2 (s), 169.2
(()-(Z)-ter t-Bu tyl 1-(Hyd r oxym eth yl)-2-[(p h en ylselen o)-
(t r iet h ylsilyl)m et h yl]cyclop r op a n e-1-ca r b oxyla t e (6). A
solution of 3 (isolated, 1.025 g, 1.95 mmol) in ether (2.5 mL) was
added to LiAlH4 (325 mg, 8.6 mmol) in ether (4 mL) with stirring
at -78 °C. The mixture was stirred for 45 min. Saturated
aqueous Na2SO4 was then added to the mixture, the mixture
was extracted with ether, and the organic phase was dried
(MgSO4) and evaporated in vacuo. The residue was dissolved in
(s), 200.0 (d, J ) 180 Hz); IR (neat) 2958, 2934, 2862, 1715 cm-1
;
MS (FAB) m/z 315 (M+ + 1). Anal. Calcd for C16H30O4Si: C,
61.11; H, 9.61. Found: C, 60.99; H, 9.62.
(()-(Z)-ter t-Bu tyl 1-((ter t-Bu tyld im eth ylsilyl)oxy)m eth -
yl-2-eth en ylcyclop r op a n e-1-ca r boxyla te (9). A solution of
n-BuLi (1.46 M in n-hexane, 1.7 mL, 2.4 mmol) was added
dropwise to a stirred and ice-cooled suspension of methylene-
triphenylphosphonium bromide (862 mg, 2.4 mmol) in THF (10
mL). The mixture was stirred at 0 °C for 15 min. A solution of
8 (309.1 mg, 0.98 mmol) in THF (4 mL) was added to the mixture
at 0 °C. The mixture was then allowed to warm to room
temperature and stirred for 3 h. After the reaction mixture was
cooled to 0 °C, water was added and the mixture was extracted
with ether. The ether layer was separated, dried (MgSO4), and
evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with hexanes:ether to give
9 (261 mg, 85%). For 9: Rf ) 0.9 (hexane:ether ) 9:1); colorless
oil; 1H NMR (200 MHz, CDCl3) δ 0.044 (s, 6H), 0.877 (s, 9H),
1.18 (dd, J ) 8.7, 4.5 Hz, 1H), 1.37-1.49 (m, 1H), 1.44 (s, 9H),
1.83 (ddd, J ) 8.7, 8.6, 8.1 Hz, 1H), 3.47 (d, J ) 10.3 Hz, 1H),
4.13 (d, J ) 10.3 Hz, 1H), 5.01 (d, J ) 10.3 Hz, 1H), 5.17 (d, J
) 16.1 Hz, 1H), 5.69 (ddd, J ) 16.1, 10.3, 8.6 Hz, 1H); 13C NMR
(50.1 MHz, CDCl3) δ -5.3 (q, J ) 119 Hz), 17.0 (t, J ) 163 Hz),
18.4 (s), 25.9 (q, J ) 125 Hz), 27.6 (d, J ) 163 Hz), 28.3 (q, J )
125 Hz), 34.0 (s), 63.8 (t, J ) 155 Hz), 80.7 (s), 115.8 (t, J ) 155
Hz), 135.7 (d, J ) 155 Hz), 170.7 (s); IR (neat) 2960, 2934, 2862,
1723, 1636 cm-1; MS (EI) m/z 312. Anal. Calcd for C17H32O3Si:
C, 65.33; H, 10.32. Found: C, 65.16; H, 10.42.
i
iPrOH (3 mL) and cooled to -30 °C, and 0.1 M NaBH4 in PrOH
(7.2 mL, 0.72 mmol) was then added to the solution. The reaction
mixture was stirred for 1 h, and then saturated aqueous Na2-
SO4 was added to the mixture. The mixture was extracted with
ether, and the organic phase was dried (MgSO4) and evaporated
in vacuo. The residue was purified by column chromatography
over silica gel eluting with hexanes:ether to give 6 (776 mg, 87%).
Crude product is pure enough for use in the next step. For 6:
Rf ) 0.15 (hexane:ether ) 4:1); colorless oil; 1H NMR (200 MHz,
CDCl3) δ 0.508-0.632 (m, 9H), 0.909 (t, J ) 7.8 Hz, 6H), 1.20
(dd, J ) 8.8, 4.4 Hz, 1H), 1.33-1.39 (m, 1H), 1.44 (s, 9H), 1.48-
1.54 (m, 1H), 2.51 (broad dd, J ) 7.2, 5.3 Hz, 1H), 2.84 (d, J )
12.2 Hz, 1H), 3.35 (dd, J ) 12.0, 7.2 Hz, 1H), 3.60 (dd, J ) 12.0,
5.3 Hz), 7.20-7.24 (m, 3H), 7.58-7.63 (m, 2H); selected observed
NOEs were between δ 1.20 and 1.33-1.39, δ 1.20 and 1.48-
1.54, δ 1.33-1.39 and 2.84, δ 1.44 and 2.84, δ 1.44 and 7.58-
7.63, δ 1.48-1.54 and 3.35, δ 1.48-1.54 and 3.60, δ 2.84 and
7.58-7.63.; 13C NMR (50.1 MHz, CDCl3) δ 3.2 (t, J ) 116 Hz),
7.6 (q, J ) 124 Hz), 23.2 (t, J ) 163 Hz), 25.3 (d, J ) 133 Hz),
28.2 (q, J ) 127 Hz), 31.0 (d, J ) 157 Hz), 33.3 (s), 67.0 (t, J )
143 Hz), 81.7 (s), 127.2 (d, J ) 159 Hz), 128.7 (d, J ) 158 Hz),
129.5 (s), 134.7 (d, J ) 164 Hz), 171.6 (s); IR (neat) 3414, 2956,
2878, 1713 cm-1; MS (EI) m/z 456; exact mass M+ 456.1578
(()-(Z)-ter t-Bu tyl 1-((ter t-Bu tyld im eth ylsilyl)oxy)m eth -
yl-2-eth ylcyclop r op a n e-1-ca r boxyla te (10). To 9 (61.7 mg,
0.2 mmol) in MeOH (0.9 mL) was added dipotassium azodicar-
boxylate (155 mg, 0.8 mmol) followed by dropwise addition of
(17) Hibbs, D. E.; Hursthouse, M. B.; J ones, I. G.; J ones, W.; Malik,
K. M. A.; North, M. Tetrahedron, 1997, 53, 17417.

Notes
J . Org. Chem., Vol. 64, No. 1, 1999 285
acetic acid (92 mg, 1.5 mmol) in MeOH (0.15 mL) at 0 °C. The
mixture was allowed to warm to room temperature and stirred
for 2 h. H2O (1.5 mL) and CH2Cl2 (3.8 mL) were added. The
organic phase was separated, dried (MgSO4), and evaporated
in vacuo. The residue was purified by column chromatography
over silica gel eluting with hexanes:ether to give 10 (59 mg, 95%).
For 10: Rf ) 0.7 (hexane:ether ) 9:1); colorless oil; 1H NMR
(200 MHz, CDCl3) δ 0.033 (s, 6H), 0.873 (s, 9H), 0.87-1.09 (m,
6H), 1.37-1.55 (m, 2H), 1.45 (s, 9H), 3.28 (d, J ) 10.3 Hz, 1H),
4.15 (d, J ) 10.3 Hz, 1H); 13C NMR (50.1 MHz, CDCl3) δ -5.3
(q, J ) 118 Hz), 14.0 (q, J ) 125 Hz), 16.7 (t, J ) 162 Hz), 18.4
(s), 20.9 (t, J ) 126 Hz), 25.9 (q, J ) 127 Hz), 26.6 (d, J ) 160
Hz), 28.2 (q, J ) 125 Hz), 32.0 (s), 65.6 (t, J ) 146 Hz), 80.2 (s),
171.8 (s); IR (neat) 2962, 2862, 1721 cm-1; MS (FAB) m/z 315
(M+ + 1); MS (EI) m/z (rel intensity) 315 (28) M+ + 1, 259 (100).
Anal. Calcd for C17H34O3Si: C, 64.92; H, 10.90. Found: C, 64.71;
H, 11.04.
(()-(E)-ter t-Bu tyl 1-(N-(ter t-Bu toxyca r bon yl)a m in o)-2-
eth ylcyclop r op a n e-1-ca r boxyla te (12). To a solution of 10
(220 mg, 0.7 mmol) in dry THF (1.40 mL) was added glacial
acetic acid (40 µL, 42 mg, 0.7 mmol) followed by a 1.0 M solution
of TBAF in THF (1.5 mL, 1.5 mmol). The reaction mixture was
stirred at 42 °C for 11 h. After the reaction mixture was cooled
to room temperature, saturated aqueous NaHCO3 solution was
added and the mixture was extracted with ether. The organic
phase was separated, dried (MgSO4), and evaporated in vacuo.
The residue was purified by column chromatography over silica
gel eluting with hexanes:ether to give (E)-tert-butyl 1-
(hydroxymethyl)-2-ethylcyclopropane-1-carboxylate (11) (133 mg,
95%) (Rf ) 0.3, hexane:ether ) 2:1). Compound 11 was converted
to 12, using the procedure described by Charette9 (yield (40%
from 11)). For 12: Rf ) 0.3 (hexane:EtOAc ) 9:1); colorless
crystals; mp 103 °C (8% EtOAc:hexane); 1H NMR (400 MHz,
CDCl3) δ 0.955 (t, J ) 7.4 Hz, 3H), 1.17 (m, 1H), 1.31-1.63 (m,
4H), 1.45 (s, 9H), 1.46 (s, 9H), 5.10 (bs, 1H); 13C NMR (100.6
MHz, CDCl3) δ 13.7, 20.4, 22.6, 28.2, 28.4, 32.7, 39.6, 79.6, 81.1,
156.0, 170.8 {the 13C NMR spectra were in accord with the
reported data for (2R,3R)-12};9 IR (KBr) 3348, 2976, 1717, 1692,
1516, 1371, 1350, 1276, 1160, 843 cm-1; MS (FAB) m/z 286 (M+
+ 1). Anal. Calcd for C15H27NO4: C, 63.13; H, 9.54; N, 4.91.
Found: C, 63.30; H, 9.59; N, 4.95.
22.2, 22.3, 25.9, 27.3, 28.3, 31.9, 33.9, 63.8, 80.5, 126.9, 132.1,
171.1; IR (neat) 2960, 2932, 2862, 1725 cm-1; MS (EI) m/z 368;
exact mass M+ 368.2748 (calcd for C21H40O3Si 368.2746).
(()-(Z)-ter t-Bu t yl
1-(((ter t-Bu t yld im et h ylsilyl)oxy)-
m eth yl)-2-(1′-h exyl)cyclop r op a n e-1-ca r boxyla te (15). To 14
(151 mg, 0.41 mmol) in MeOH (1.8 mL) was added dipotassium
azodicarboxylate (318 mg, 1.6 mmol) followed by dropwise
addition of acetic acid (184 mg, 3.1 mmol) in MeOH (0.3 mL) at
0 °C. The mixture was allowed to warm to 50 °C and stirred for
48 h. Dipotassium azodicarboxylate (318 mg, 1.6 mmol) and
acetic acid (184 mg, 3.1 mmol) in MeOH (0.3 mL) were added to
the reaction mixture, and the reaction was stirred at 50 °C for
an additional 26.5 h. Dipotassium azodicarboxylate (318 mg, 1.6
mmol) and acetic acid (184 mg, 3.1 mmol) in MeOH (0.3 mL)
were then added to the mixture and stirred at 50 °C for an
additional 1.5 h (disappearance of 14 was checked by GC). H2O
(1.8 mL) was added to the reaction mixture, followed by
extraction with CH2Cl2. The organic phase was separated, dried
(MgSO4), and evaporated in vacuo. The residue was purified by
column chromatography over silica gel eluting with hexanes:
ether to give 15 (187 mg, 89%). For 15: Rf ) 0.7 (hexane:ether
) 9:1); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 0.028 (s,
3H), 0.030 (s, 3H), 0.865-0.889 (m, 4H), 0.872 (s, 9H), 1.03-
1.09 (m, 2H), 1.23-1.40 (m, 8H), 1.41-1.44 (m, 2H), 1.45 (s, 9H),
3.30 (d, J ) 10.3 Hz, 1H), 4.13 (d, J ) 10.3 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ -5.3 (q), 14.2 (q), 16.8 (t), 18.4 (s), 22.7
(t), 25.0 (d), 26.0 (q), 27.6 (t), 28.3 (q), 29.2 (t), 29.8 (t), 32.0 (s),
32.0 (t), 65.5 (t), 80.2 (s), 171.9 (s); 13C multiplicities were
determined by DEPT; IR (neat) 2960, 2930, 2862, 1721 cm-1
;
MS (EI) m/z (rel intensity) 371 (4.3) (M+ + 1), 297 (14), 259 (100).
(()-(Z)-ter t-Bu tyl 1-(Hyd r oxym eth yl)-2-(1′-h exyl)cyclo-
p r op a n e-1-ca r boxyla te (16). Compound 16 was prepared from
15 using the procedure described for 11 (yield (95%)). For 16:
Rf ) 0.5 (hexane:ether ) 1:1); colorless oil; 1H NMR (400 MHz,
CDCl3) δ 0.860-0.918 (m, 4H), 1.12-1.20 (m, 2H), 1.27-1.39
(m, 8H), 1.43-1.49 (m, 2H), 1.48 (s, 9H), 2.63 (dd, J ) 8.7, 4.9
Hz, 1H), 3.35 (dd, J ) 11.9, 8.7 Hz, 1H), 3.68 (dd, J ) 11.9, 4.9
Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.2, 18.9, 22.7, 27.6,
27.7, 28.3, 29.2, 29.8, 31.8, 32.0, 68.1, 81.4, 173.0; IR (neat) 3418,
2962, 2930, 2862, 1719 cm-1; MS (EI) m/z (rel intensity) 215
(1.3) (M+ - 41), 200 (100), 183 (78).
(()-Cor on a m ic Acid (13). To a solution of 1.7 N HCl in
MeOH (3.4 mL, 5.8 mmol) at 0 °C was added 12 (24 mg, 0.08
mmol), and the mixture stirred for 24 h at the same temperature,
followed by removal of the solvent. The residue was dissolved
in H2O (0.25 mL), loaded on a Dowex column (H+-form, 50W-8
100-200 mesh, 0.9 × 2.4 cm), and eluted with H2O until neutral
and chloride-free (AgNO3 test). The product was then eluted with
2 N NH3/H2O (8 mL). Evaporation gave 13 (7 mg, 71%).10 For
13: white solid; mp sublimed at ca. 170-190 °C; 1H NMR (400
MHz, D2O) δ 0.867 (t, J ) 7.2 Hz, 3H), 1.20-1.25 (m, 2H), 1.36-
1.62 (m, 3H); 13C NMR (100.6 MHz, D2O) δ 13.6, 17.9, 20.8, 28.6,
40.6, 175.4; IR (KBr) 3400, 3150-2950, 2100, 1640-1522, 1441,
1396, 1296, 1222 cm-1; MS (FAB) m/z 130 (M+ + 1).
(()-(E)-ter t-Bu t yl 1-((N-ter t-Bu t oxyca r b on yl)a m in o)-2-
(1′-h exyl)cyclop r op a n e-1-ca r boxyla te (17). Compound 16 (76
mg, 0.30 mmol) was dissolved in a mixture of CH3CN (1.0 mL),
CCl4 (1.0 mL), and H2O (1.3 mL). NaIO4 (254 mg, 1.2 mmol)
was then added followed by RuCl3‚xH2O (3 mg, ca. 0.014 mmol).
After 2.5 h of stirring at room temperature, the solution was
diluted with CH2Cl2, the layers were separated, and the aqueous
layer was extracted with CH2Cl2 three times. The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
The residue was filtered on a short plug of silica gel that was
washed with EtOAc:hexane:AcOH (69:30:1) to give the acid (72
mg, 90%). To a solution of the acid (71 mg, 0.26 mmol) in toluene
(3.2 mL) at 0 °C was added triethylamine (0.17 mL, 125 mg, 1.2
mmol) followed by diphenylphosphoryl azide (136 µL, 173 mg,
0.63 mmol). The ice bath was removed, and the reaction mixture
was stirred for an additional 3.5 h at room temperature. Ether
and H2O were then added, and the layers were separated, and
the aqueous layer was extracted with ether twice. The combined
organic layers were washed with saturated aqueous NaHCO3
and saturated aqueous NaCl. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography over silica gel eluting with hexane:
ether to give the acyl azide (66 mg, 85%). The acyl azide (66
mg, 0.22 mmol) in tert-butyl alcohol (2.1 mL) was heated at 110
°C for 48 h. The tert-butyl alcohol was evaporated in vacuo, and
the residue was purified by column chromatography over silica
gel eluting with hexane:ether (9:1) to give 17 (65 mg, 85%). For
17: Rf ) 0.4 (hexane:ether ) 2:1); colorless crystals; mp 83 °C
(10% ether/hexane); 1H NMR (400 MHz, CDCl3) δ 0.873 (t, J )
6.7 Hz, 1H), 1.19-1.61 (m, 13H), 1.449 (s, 9H), 1.454 (s, 9H),
5.08 (bs, 1H); 13C NMR (100.6 MHz, CDCl3) δ 14.1 (q), 22.7 (t),
22.7 (t), 27.0 (t), 28.1 (q), 28.4 (q), 29.1 (t), 29.4 (t), 30.8 (d), 31.9
(t), 39.5 (s), 79.5 (s), 81.0 (s), 156.0 (s), 170.8 (s); 13C multiplicities
were determined by DEPT; IR (neat) 3346, 2926, 1723, 1694
cm-1; MS (FAB) m/z 342 (M+ + 1). Anal. Calcd for C19H35NO4:
C, 66.83; H, 10.33; N, 4.10. Found: C, 66.44; H, 10.34; N, 4.08.
(()-(Z)-ter t-Bu t yl
1-(((ter t-Bu t yld im et h ylsilyl)oxy)-
m eth yl)-2-(1′-(Z)-h exen yl)cyclop r op a n e-1-ca r boxyla te (14).
A solution of n-BuLi (1.54 M in n-hexane, 1.04 mL, 1.6 mmol)
was added dropwise to a stirred and ice-cooled suspension of
pentylenetriphenylphosphonium bromide (663 mg, 1.6 mmol) in
THF (5.4 mL). The mixture was stirred at 0 °C for 15 min. A
solution of 8 (194 mg, 0.62 mmol) in THF (1.2 mL) was added
to the mixture at 0 °C. The mixture was allowed to warm to
room temperature and stirred for 2.5 h. After the reaction
mixture was cooled to 0 °C, water was added and the mixture
was extracted with ether. The ether layer was separated, dried
(MgSO4), and evaporated in vacuo. The residue was purified by
column chromatography over silica gel eluting with hexane:ether
to give 14 (205 mg, 90%). For 14: Rf ) 0.6 (hexane:ether ) 9:1);
pale yellow oil (olefin Z:E ) ca. 9:1); 1H NMR (400 MHz, CDCl3)
(peaks for the major Z olefin isomer) δ 0.045 (s, 3H), 0.051 (s,
3H), 0.882 (s, 9H), 0.900 (t, J ) 7.0 Hz, 3H), 1.19 (dd, J ) 8.8,
4.4 Hz, 1H), 1.29-1.39 (m, 5H), 1.43 (s, 9H), 1.98 (ddd, J ) 8.9,
8.8, 7.6 Hz, 1H), 2.11 (dtd, J ) 7.6, 7.2, 1.4 Hz, 2H), 3.53 (d, J
) 10.3 Hz, 1H), 4.10 (d, J ) 10.3 Hz, 1H), 5.24 (ddt, J ) 10.4,
8.9, 1.4 Hz, 1H), 5.45 (dt, J ) 10.4, 7.6 Hz, 1H); selected observed
NOE is between δ 5.24 and 5.45; 13C NMR (100.6 MHz, CDCl3)
δ (peaks for the major Z olefin isomer) -5.3, 14.0, 17.6, 18.4,

286 J . Org. Chem., Vol. 64, No. 1, 1999
Notes
(()-(E)-1-Am in o-2-h exylcyclop r op a n e-1-ca r boxylic Acid
(18). Compound 18 was prepared from 17 using the procedure
described for 13 (yield (80%)). For 18: amorphous white solid;
mp 228-230 °C (dec); 1H NMR (400 MHz, CF3CO2D) δ 0.729 (t,
J ) 6.9 Hz, 3H), 1.12-1.42 (m, 8H), 1.56-1.69 (m, 3H), 1.75-
1.79 (m, 1H), 1.91-1.99 (m, 1H); 13C NMR (100.6 MHz, CF3-
CO2D) δ 14.0 (q), 22.2 (t), 23.7 (t), 28.0 (t), 30.1 (t), 30.2 (t), 32.7
(d), 32.9 (t), 41.4 (s), 176.1 (s); 13C multiplicities were determined
by DEPT; IR (KBr) 3420, 3100-2962, 2924, 2858, 1638-1524,
1439, 1408, 1299, 1218 cm-1; MS (FAB) m/z 186 (M+ + 1).
(()-(Z)-1-ter t-Bu t yl 2-Met h yl 1-(((ter t-Bu t yld im et h yl-
silyl)oxy)m eth yl)cyclopr opan e-1,2-dicar boxylate (19). Com-
pound 7 (containing a small amount of impurity arising from
cyclobutane 4)13 (200 mg, ca. 0.35 mmol) was dissolved in a
mixture of CH3CN (6.0 mL), CCl4 (6.0 mL), and H2O (3.0 mL).
NaIO4 (653 mg, 3.05 mmol) was then added followed by RuCl3‚
xH2O (7 mg, ca. 0.033 mmol). After 5 h of stirring at room
temperature, the solution was diluted with CH2Cl2. The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 three times. The combined organic layers were dried (Na2-
SO4) and concentrated in vacuo. The residue was purified by
column chromatography over silica gel eluting with EtOAc:
hexane:AcOH (69:30:1) to give the acid (79 mg, ca. 68%) (Rf )
0.5, hexane:ether ) 1:1). The acid (79 mg, 0.24 mmol) was
treated with diazomethane in ether. Purification by column
chromatography (silica gel, hexanes:ether) gave 19 (57 mg, 69%).
For 19: Rf ) 0.5 (hexane:ether ) 4:1); pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 0.041 (s, 3H), 0.049 (s, 3H), 0.869 (s, 9H),
1.24 (dd, J ) 8.6, 4.6 Hz, 1H), 1.43 (s, 9H), 1.69 (dd, J ) 6.5, 4.6
Hz, 1H), 1.99 (dd, J ) 8.6, 6.5 Hz, 1H), 3.67 (s, 3H), 3.69 (d, J )
10.3 Hz, 1H), 4.00 (d, J ) 10.3 Hz, 1H); selected observed NOEs
were between δ 1.24 and 1.69, δ 1.24 and 1.99, δ 1.43 and 3.67,
δ 1.99 and 3.69; 13C NMR (100.6 MHz, CDCl3) δ -5.41, -5.39,
15.0, 18.3, 24.0, 25.9, 28.0, 35.1, 51.9, 62.8, 81.3, 169.1, 171.0;
IR (neat) 2956, 2934, 2862, 1740, 1730 cm-1; MS (FAB) m/z 345
(M+ + 1). Anal. Calcd for C21H42O3Si: C, 68.05; H, 11.42.
Found: C, 67.57; H, 11.35.
2984, 1734, 1717 cm-1; MS (FAB) m/z 231 (M+ + 1); MS (EI)
m/z (rel intensity) 175 (25) (M+ - 55), 157 (100) 143 (40).
(()-(E)-1-ter t-Bu tyl 2-Meth yl 1-((N-ter t-Bu toxyca r bon yl)-
a m in o)cyclop r op a n e-1,2-d ica r boxyla te (21). Compound 20
(125 mg, 0.54 mmol) was dissolved in a mixture of CH3CN (5.7
mL), CCl4 (5.7 mL), and H2O (7.3 mL). NaIO4 (1.393 g, 6.5 mmol)
was then added followed by RuCl3‚xH2O (15 mg, ca. 0.072 mmol).
After 5 h of stirring at room temperature, the solution was
diluted with CH2Cl2. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 three times. The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
The residue was filtered through a short plug of silica gel that
was washed with EtOAc:hexane:AcOH (69:30:1) to give the acid
(104 mg, 78%). To a solution of the acid (51 mg, 0.21 mmol) in
tert-butyl alcohol (1.0 mL) was added triethylamine (32.0 µL,
23 mg, 0.23 mmol) followed by diphenylphosphoryl azide (48.6
µL, 62 mg, 0.23 mmol). The mixture was heated at 110 °C for
5.5 h. After cooling to room temperature, the reaction mixture
was diluted with ether. The organic layer was washed with
saturated aqueous NaHCO3 and saturated aqueous NaCl. The
organic layer was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by column chromatography over silica gel
eluting with hexane:ether to give 21 (25 mg, 38%). For 21: Rf )
0.4 (hexane:ether ) 1:2); pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ 1.43 (s, 9H), 1.42-1.48 (m, 1H), 1.46 (s, 9H), 2.04 (m,
1H), 2.26 (dd, J ) 9.0, 9.0 Hz, 1H), 3.70 (s, 3H), 5.16 (bs, 1H);
selected observed NOEs were between δ 1.42-148 and 2.04, δ
1.43 and 3.70, δ 1.46 and 2.26; 13C NMR (100.6 MHz, CDCl3) δ
20.2 (t), 27.9 (q), 28.3 (q), 31.6 (d), 40.8 (s), 52.2 (q), 80.4 (s),
82.3 (s), 155.5 (s), 168.5 (s), 168.6 (s); 13C multiplicities were
determined by DEPT; IR (neat) 3350, 2982, 1734, 1715, 1696
cm-1; MS (EI) m/z 315; exact mass M+ 315.1696 (calcd for
C15H25O6N 315.1682).
Ack n ow led gm en t. We thank the Kaneko-Narita
Research Foundation for generous financial support.
(()-(Z)-1-ter t-Bu tyl 2-Meth yl 1-(Hyd r oxym eth yl)cyclo-
p r op a n e-1,2-d ica r boxyla te (20). Compound 20 was prepared
from 19 using the procedure described for 11 (yield (95%)). For
20: Rf ) 0.1 (hexane:ether ) 2:1); pale yellow oil; 1H NMR (400
MHz, CDCl3) δ 1.17 (dd, J ) 8.7, 5.0 Hz, 1H), 1.45 (s, 9H), 1.83
(ddd, J ) 6.9, 5.0, 0.7 Hz, 1H), 2.02 (dd, J ) 8.7, 6.9 Hz, 1H),
2.50 (bs, 1H), 3.57 (bdd, J ) 11.7, 6.8 Hz, 1H), 3.67 (s, 3H), 3.71
(bdd, J ) 11.7, 2.9 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 16.7,
26.7, 28.0, 34.7, 52.1, 66.4, 82.3, 169.8, 170.2; IR (neat) 3500,
Su p p or t in g In for m a t ion Ava ila b le: Copies of 2D-
NOESY spectra for compounds 7 and 21 and HMBC spectra
for 21 (10 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9810821